Kobophenol A Inhibits Binding of Host ACE2 Receptor with Spike RBD Domain of SARS-CoV-2, a Lead Compound for Blocking COVID-19

Gangadevi, Suresh; Badavath, Vishnu Nayak; Thakur, Abhishek; Yin, Na; De Jonghe, Steven; Acevedo, Orlando; Jochmans, Dirk; Leyssen, Pieter; Wang, Ke; Neyts, Johan; Yujie, Tao; Blum, Galia

[Image: see text] In the search for inhibitors of COVID-19, we have targeted the interaction between the human angiotensin-converting enzyme 2 (ACE2) receptor and the spike receptor binding domain (S1-RBD) of SARS-CoV-2. Virtual screening of a library of natural compounds identified Kobophenol A as a potential inhibitor. Kobophenol A was then found to block the interaction between the ACE2 receptor and S1-RBD in vitro with an IC(50) of 1.81 ± 0.04 μM and inhibit SARS-CoV-2 viral infection in cells with an EC(50) of 71.6 μM. Blind docking calculations identified two potential binding sites, and molecular dynamics simulations predicted binding free energies of −19.0 ± 4.3 and −24.9 ± 6.9 kcal/mol for Kobophenol A to the spike/ACE2 interface and the ACE2 hydrophobic pocket, respectively. In summary, Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19.